Astrogliopathology of depression: insights from human
and rodent studies
Picture adapted from Gillian Blease / Getty Images
by: Tjitske de Graaf studentnumber: 0513725
supervisors: Sabine Spijker & Mark Verheijen co-assessor: Paul Lucassen
VU - Center for Neurogenomics and Cognitive Research UvA - Structural and Functional Plasticity of the Nervous System
Abstract – Major depressive disorder (MDD) is a severe and prevalent psychopathology, with a large burden on society. For effective treatment, the underlying neurobiological mechanism needs to be understood. Although the
current pharmacotherapy for MDD is based upon the monoamine hypothesis, there are strong indications that the neurobiology of MDD is more complex than an imbalance of neurotransmitters. Recent evidence suggests a major role for glial cells abnormalities. First, studies that examined post-mortem tissues from depressive patients found significant decline in glial cell density in multiple brain regions. Secondly, accumulating evidence suggest that glial cells are far more functionally involved in brain processes that previously thought. One specific glial cell, the astrocyte, is thought to be a key player in essential all processes involving neuronal functioning and survival. Astroglial cells communicate directly with neurons via the tripartite synapse and play a major role in glutamate homeostasis. Here I extensively discuss the current findings and propose a model for astrogliopathology as a component of the pathophysiology of MDD.
Contents
1 Introduction...4
2 Major depressive disorder, a devastating disease...6
2.1 Clinical diagnosis of severe depression...6
2.2 MDD: from treatment strategies to the monoaminergic hypothesis...7
3. Neurobiology of depression: new insights...11
3.1 The HPA-axis dysregulation hypothesis of depression...12
3.2 The impaired neurogenesis hypothesis of depression...13
3.3 The distorted neuroplasticity hypothesis of depression...13
3.4 The inflammatory hypothesis of depression...14
3.5 The GABA deficit hypothesis of depression...15
3.6 The glutamate excitotoxicity hypothesis of depression...15
3.7 The gliopathology hypothesis of depression...16
4 Glial cells: new insights...18
4.1 Astrocytes, oligodendrocytes and microglia...18
4.2 Astrogliopathology and MDD...22
5 Animal models of depression...24
6 How the dysfunction of astrocytes can contribute to the pathophysiology seen in MDD...31
6.1 The tripartite synapse...32
6.2. The glutamergic tripartite synapse...33
6.3. Potential therapeutic target...35
Conclusion...36
1 Introduction
Depression is a common multifaceted psychiatric disorder affecting over 350 million people worldwide (Mathers, Fat, & Boerma, 2008). The lifetime prevalence is in the range of 10-15% and increases yearly (Kessler, Berglund, Demler, & et al, 2003). It is estimated by the World Health Organization that in 2020 it will become the second largest cause of global disease following ischemic heart disease (Moussavi et al., 2007).
Depression is characterized primarily by a pervasive depressed mood, often accompanied by a loss of interest, lack of motivation and the inability to experience joy and pleasure (Nestler et al., 2002). Not only the state of mood is affected, but also vital functions such as appetite, sexuality, sleep and memory. When left untreated, depression can become recurrent or chronic and decrease quality of life. In severe cases it can even lead to suicide (Bostwick & Pankratz, 2014). Depression furthermore increases the risk of developing a drug or alcohol addiction and augments the risk of a number of health issues, such as cardiovascular disease, diabetes, obesity and cancer (Jo, Zhang, Emrich, & Dietrich, 2015).
The costs of depression are also becoming an increasingly economic burden on society (Olesen, Gustavsson, Svensson, Wittchen, & Jönsson, 2012). In the EU alone the costs were estimated at €92 billion in 2010, affecting over 30 million people. The majority of these costs are indirect to medical cost, for example lost work productivity due to sick leave and the increased risk for unemployment. Depression can result in people withdrawing themselves from their families, social life and work. As a result of the heavy burden on both individuals and society, depression is a subject for many research projects.
While the exact cause of depression is unknown, there are a number of risk factors associated with its development (Krishnan & Nestler, 2008a). Generally, depression is not the result of a single event but of a combination of stressful life events and personal susceptibility, genetic, and environmental factors (Manji, Drevets, & Charney, 2001; Sullivan, Neale, & Kendler, 2014). As a result, the causes of depression are likely to be different for different people. The main risk factor identified is earlier exposure to stressful live events, for example: divorce, job loss, physical, or psychological abuse. Such events have
occurred prior to developing depression in around 80 percent of the clinically depressed patients (Kessler et al., 2003; Manji et al., 2001).
The most common treatments for depression are psychotherapy, pharmacotherapy or a combination of both (Kupfer, Frank, & Phillips, 2012). Although both types of therapy have been proven to be effective in some of the patients, a large number of depressed persons appears to be treatment-resistant. Furthermore, it takes several weeks for the drugs to take effect. In addition, antidepressant drugs are known for their many side-effects. As a result some of the patients discontinue their treatment.
The majority of the currently prescribed drugs operates according to the monoamine hypothesis (Sanacora & Banasr, 2013). However in the past years it became more and more clear that this hypothesis is too simplistic and cannot explain all the underlying biological mechanisms. Therefore, the focus of research has been re-directed towards altered receptor expression and disrupted neural circuitries and this has generated new theories regarding the neurobiology of MDD.
One of these promising new theories involves glial cells abnormalities (Grazyna Rajkowska, 2000). Postmortem tissue from depressed patients showed severe alteration in glial cells, whereas neurons showed little or no morphological changes. Glial cells were until recently seen as mere support cells (Sofroniew & Vinters, 2010a). However in recent years it has been discovered that these cells are far more functionally active and are far more involved in brain homeostasis and signaling that originally thought. Of the three types of glia that occur in the central nervous system, astrocytes are most often implicated as a source of glial pathology in depression (G Rajkowska & Stockmeier, 2013).
Summary: Depression has a huge impact on the patient itself, but also on its
family, work environment, and the society as a whole. Treatment is often difficult, therefore a better understanding of the underlying mechanisms is needed. One of the promising research endeavors looks at glial cell abnormalities. In this review I will look at supporting evidence from both human and animal studies for the dysregulation of astroglial cells as the potential pathophysiological pathway of depression.
2 Major depressive disorder, a devastating disease
2.1 Clinical diagnosis of severe depression
Depression ranges in seriousness from mild, temporary episodes of sadness to severe, persistent depression. The depressive disorders which are clinically diagnosed include disruptive mood dysregulation disorder, major
depressive disorder (MDD), persistent depressive disorder
(dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder (Association, 2013). MDD represents the most classic condition in this group of disorders.
MDD is usually determined by the use of extensive questionnaires based upon the Diagnostic and Statistical Manual of Mental Disorders. According to the latest edition of this manual, the DMV-V, MDD is defined by one or more major depressive episodes and the lifetime absence of mania (Association, 2013). A depressive episode should at least last for 2 weeks and requires the presence of one or both of the core symptoms: depressed mood and anhedonia. In addition to the core symptoms, a patient should show a minimum of three of the other listed symptoms. These include: change in weight or appetite, insomnia or hypersomnia, psychomotor retardation or agitation, loss of energy, impaired concentration or indecisiveness and suicidal thoughts. Although the frequency may vary between symptoms, most have to be present “nearly every day”. The symptoms must be severe enough to cause noticeable problems in relationships with others and day-to-day activities such as work or school.
The symptomatology of MDD is heterogeneous and multidimensional. As a result, one patient can exhibit signs of overeating, too much sleep and being lethargic, whereas another patient may have insomnia, while being underfed and agitated. Attempts have been made to establish subtypes of depression based upon defined sets of symptoms (Nestler et al., 2002). These include melancholic depression, reactive depression psychotic depression, atypical depression, and dysthymia. Initial studies have started to investigated whether different biological systems are involved in the different depressive subtypes. Supporting evidence that different neural circuitry, HPA-axis and inflammatory factors are involved in melancholic and atypical depression (Lamers et al., 2013).
2.2 MDD: from treatment strategies to the monoaminergic hypothesis
The most common treatment options for depression are pharmacotherapy or psychotherapy. Cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT) are the main forms of psychotherapy and are proven to be effective in treating depression (Krupnick et al., 1996). CBT is based upon recognizing negative behaviors and thought patterns that lead to depression and focused on changing these destructive patterns. IPT is more focused on damaged relationship that contribute to the depressed mood. Psychotherapy has been proven to be effective in mild to moderate depression.
In more severe cases of depression, such as MDD, antidepressant medication is the main treatment strategy (Kupfer et al., 2012). Pharmacotherapy can be combined with psychotherapy, but whether monotherapy or a combined strategy is the better option is still a topic of heavy discussion. Other less mainstream treatment options include electroconvulsive shock therapy (ECT) for the severe treatment resistant patients.
The first antidepressants were discovered by chance, when a drug targeted for tuberculosis was found to elevate mood in depressive patients (Wong & Licinio, 2001). Around the same time, drugs that had antidepressant activity were found to increase extracellular levels of serotonin and norepinephrine. As a result of these findings Schildkraut proposed in 1965 the first biochemical theory to explain how deficits in monoamines cause depression, and this became known as the monoaminergic hypothesis (Schildkraut, 1965). This hypothesis states that the deficits of specific monoamines (or neurotransmitters) cause depression. Specifically the neurotransmitters serotonin and norepinephrine, and to a lesser degree dopamine, were found to be the culprits.
The neurotransmitter serotonin plays an important role in the regulation of mood, emotion, sleep and sexual and eating behavior. Post mortem studies showed decreased levels of this neurotransmitter in some MDD patients (Blier & Montigny, 1994). An important role for tryptophan, a serotonin precursor, was indicated in depletion studies. Depletion of tryptophan induces depressive symptoms in healthy subjects (Delgado et al., 1994). Furthermore animal studies
revealed that almost all long-term antidepressant medications as well as ECT increases serotonergic neurotransmission.
In addition, drugs that cause a depletion of catecholamines such as (nor)epinephrine and their precursor dopamine, were found to have depressive moods as side effects (Schildkraut, 1965). Catecholamines play an important role in reward, inner drive, and motivation. Several antidepressants have been shown to increase norepinephrine levels by preventing the breakdown of norepinephrine or by inhibiting its uptake (Hollister & Claghorn, 1993).
The proposed treatment of depression according to the monoaminergic hypothesis was to increase the availability of the monoamines in the brain. The first clinically used antidepressants (AD) available, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) are based upon this principle. Both drugs operate by elevating monoamine levels (Kandel ER Schwartz JH, 2000). Monoamine Oxidase Inhibitors (MAOIs), inhibit the breakdown of the monoamines, thus prolonging the time that the monoamines can be active. In contrast, tricyclic antidepressants (TCAs) increase the duration of availability of the monoamines in the synaptic cleft by blocking their reuptake. However, beside the reported positive effects, both MAOIs and TCAs were found to have extreme, sometimes even fatal, side-effects in some patients.
Several new classes of antidepressant have since been introduced, of which Selective Serotonin Reuptake Inhibitors (SSRIs) have currently become the first-line prescribed drugs for MDD patients. SSRIs (such as fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram) have relatively few side effects and show high efficacy. These drugs are also based upon the monoaminergic hypothesis, and operate by blocking the reuptake of serotonin in the synapse (Hasler, 2010).
However, despite the efficacy of SSRIs, only a third of MDD patients achieve complete remission following chronic treatment (Krishnan & Nestler, 2008b). Remission rates of at best 30-40 percent have been observed. Another third of MDD patients only experiences partial relief of the symptoms, while the last third of MDD patients show no response at all (Warden, Rush, Trivedi, Fava, & Wisniewski, 2007)]. Drug efficacy trials are seldom conducted on subtype-segregated groups, which might explain the discrepancy in the efficacy of these drugs amongst different patients. Since current available drugs are based upon
the same hypothesis, it is possible that only one type of depression is being treated. Furthermore, it was found that placebo treatment seems to work as good as antidepressants in mildly depressed patients (Zimmerman, Posternak, & Chelminski, 2002).
Although the neuropharmacological actions of antidepressants are well characterized, what precisely causes the relief of depressive symptoms is not yet known (Arroll et al., 2009). The monoamine levels are elevated within two to three days of antidepressant administration, whereas antidepressant effects are not observed until three to five weeks after drug administration. This therapeutic delay forms an apparent discrepancy with the monoaminergic hypothesis.
The robustness of the monoaminergic hypothesis as the only biological mechanism underlying MDD pathology was further impaired when research failed to find convincing evidence for the dysfunction of one of the monoamine systems in MDD (Delgado, 2000). Depletion of serotonin or norepinephrine does not lead to depressive symptoms in healthy subjects, or worsen the symptoms in non-medicated MDD patients (Booij, der Does, & Riedel, 2003). Drugs that enhance the transmission of monoamines, for example amphetamine and cocaine, do not have antidepressant properties (Rang, 2007). All of these phenomena could not be explained by the monoaminergic hypothesis.
The question rises whether current antidepressants function through first or second order effect, or if they work at all. Since several years the monoaminergic hypothesis seems not to be the only explanation for the underlying neurobiology of depression. Novel research directions focusing on disrupted neural circuitries generated new theories of the neurobiology of MDD.
Summary: Current therapeutic strategies are based upon the monoaminergic
hypothesis and although these treatments are beneficial for many MDD patients there are multiple indications that the underlying pathophysiology extends beyond this theory. It is possible that the diminished levels of monoamines are the downstream effect of other processes. This could explain the time gap between therapy initiation and therapeutic effectivity. In the following chapter I will review the current theories on the pathophysiology of MDD.
3. Neurobiology of depression: new insights
The understanding that the monoaminergic theory was not complex enough to describe the pathology underlying depression sparked an interest for new theories that explain the mechanism behind the etiology of MDD. Several decades of research from neuroimaging studies, postmortem studies and animal models of depression have lead to multiple different hypotheses to try to explain the pathophysiology of depression. Although the new research endeavors have not yet replaced the monoaminergic hypothesis as leading theory, they uncovered some very promising findings. Here I will briefly review the different hypotheses and their strengths and limitations.
3.1 The HPA-axis dysregulation hypothesis of depression
Stress is thought to play a major contributory role in the process of developing MDD. The majority of the MDD patients went through
a stressful life event prior in their lives. The main mechanism by which the brain reacts to stress is the activation of the hypothalamus-pituitary-adrenal (HPA) axis (Nestler et al., 2002). In a normal stress response, a cascade of corticotrophin-releasing hormone (CRH/CRF) and vasopressin induces the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland which in turn leads to an increase in release of glucocorticoids from the adrenal glands. Together, these hormones and neuropeptides augment physiological responses and result in the release of pro- and anti-inflammatory cytokines. The activity of the HPA axis is regulated by several negative feedback mechanisms. A large number of clinical and basic researches indicate that MDD is associated with a maladaptive response to stress, due
to dysfunction of the HPA axis (Watson & Mackin, 2006). However, the major problem with the HPA-axis hyperactivity hypothesis is that changes of HPA axis activity is only found in a part of the patient population. In addition, dysfunction of the HPA axis does also not automatically result in depressive symptoms.
Figuur 1 HPA axis; the hypothalamus secretes corticotrophin-releasing hormone (CRH/CRF) and vasopressin, which in turn stimulate the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland, which in turn stimulates the synthesis of glucocorticoids. Glucocorticoids feed back at the level of the hippocampus, hypothalamus and pituitary to dampen excess activation of the HPA axis. figure from (Hyman, 2009)
3.2 The impaired neurogenesis hypothesis of depression
One of the most consistent findings of neuroanatomical changes that occur in people that suffer from MDD is reduced grey matter volume of the hippocampus and frontal cortex (Drevets, Price, & Furey, 2008). One of the possible explanations for these changes in volume is reduced neurogenesis (Lucassen et al., 2010).
The hippocampus plays an important role in memory encoding and one of the symptoms associated with MDD is cognitive dysfunction, which could be associated with reduced hippocampal neurogenesis. Animal studies found that both chronic and acute stress reduced the level of neurogenesis (Cameron & Gould, 1994), whereas chronic administration of antidepressants was found to induce neurogenesis (Malberg, Eisch, Nestler, & Duman, 2000). These studies sparked the neurogenesis hypothesis that argued for diminished neurogenesis as cause for depression.
A direct link between depression and neurogenesis has yet to be found. It is not yet known whether the observed changes are the cause or the result of depression. More importantly, the structural changes do not necessarily mean a functional role during depression.
3.3 The distorted neuroplasticity hypothesis of depression
Neuroplasticity is the brain’s ability to reorganize itself by neuronal remodeling, the formation of novel synapses. The concept of neuroplasticity has replaced the old idea that the brain is a physiologically static organ. The changes that occur during neuroplasticity are the result of changes in behavior, environment, neural processes, emotion, cognition, or injury (Pascual-Leone et al., 2011). As a result, stress thus has the ability to interfere with neuroplasticity. The neuroplasticity hypothesis is based upon the idea that stress leads to distorted communication of neuronal networks. This idea is supported by findings that antidepressant restore neuronal connectivity and induce neuroplasticity (Fuchs, Czéh, Kole, Michaelis, & Lucassen, 2004).
Neuroplasticity requires neurotrophic factors such as brain-derived neurotrophic factor (BDNF). BDNF is the most abundant and widely distributed growth factor in the brain and facilitates neuronal survival and synaptic plasticity. The neuroplasticity hypothesis of depression is supported by findings of low
BNDF levels in postmortem material from MDD patients (Karege et al., 2002) and that antidepressant treatments increase BDNF levels (B.-H. Lee & Kim, 2010). However low BDNF levels itself does not automatically result in depressive behaviors, so a causal connection cannot be established.
3.4 The inflammatory hypothesis of depression
Another promising theory is the inflammatory hypothesis of depression. This is based upon the idea that the immune system is involved in the development of depression, through the release of pro-inflammatory cytokines following internal or external stressors. The administration of pro-inflammatory cytokines was found to induce depressive like symptoms, both in humans and animals (Miller, Maletic, & Raison, 2009). Some antidepressant drugs have demonstrated to reduce levels of pro-inflammatory cytokines (Song, Halbreich, Han, Leonard, & Luo, 2009). Furthermore, people that suffer from inflammation afflicted diseases such as cardiovascular disease, multiple sclerosis or rheumatoid arthritis are three times more likely to develop depression.
Although multiple findings suggest an elevated immune response in people suffering from depression, results regarding the antidepressant effects of anti-inflammatory drugs have been mixed.
3.5 The GABA deficit hypothesis of depression
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system and plays a prominent role in stress control. A series of magnetic resonance spectroscopy (MRS) studies consistently showed reduction of GABA concentrations in MDD patients (Hasler et al., 2007), resulting in the GABAergic deficit hypothesis. However this hypothesis is challenged by the lack of effect of GABAergic drug on core symptoms of MDD (Luscher, Shen, & Sahir, 2011).
Figuur 2 Stress-induced activation of the inflammatory response. Catecholamines released can increase NF-κB DNA binding in relevant immune cell types, including macrophages, resulting in the release of inflammatory mediators that promote inflammation. Proinflammatory cytokines, in turn, can access the brain, induce inflammatory signaling pathways including NF-κB, and ultimately contribute to altered monoamine metabolism, increased excitotoxicity, and decreased production of relevant trophic factors. Picture taken from (Miller et al., 2009)
3.6 The glutamate excitotoxicity hypothesis of depression
Glutamate, the main excitatory neurotransmitter is also indicated in the etiology of MDD. GABA and glutamate levels are intrinsically linked, as glutamate is the metabolic precursor of GABA. Glutamate plays a central role in synaptic plasticity, learning, and memory (Sanacora, Rothman, Mason, & Krystal, 2003). Glutamate is toxic in high concentrations and can ultimately lead to neuronal death. Abnormal glutamate levels were found in depressed subjects as determined by MRS studies (Hasler et al., 2007) and post mortem studies (Hashimoto, Sawa, & Iyo, 2007). Furthermore, inhibitors of glutamate release exhibited antidepressant properties (Kendell, Krystal, & Sanacora, 2005). The recreational drug ketamine, which operates on the glutamatergic system, was even found to have direct (3-4 hours after administration) antidepressant properties in treatment resistant patients (Berman et al., 2000; Zarate et al., 2006).
3.7 The gliopathology hypothesis of depression
One of the most consistent findings in MDD postmortem studies are changes in glial cell density and size. In multiple brain areas, a reduction of brain glial cell density was found including the prefrontal cortex (Grazyna Rajkowska, Miguel-Hidalgo, Wei, Dilley, Pittman, Meltzer, Overholser, Roth, & a. Stockmeier, 1999), hippocampus (Bowley, Drevets, Öngür, & Price, 2002), amygdala (Hamidi, Drevets, & Price, 2004), anterior cingulate cortex (Cotter, Mackay, Landau, Kerwin, & Everall, 2001; Ongür, Drevets, & Price, 1998) and orbitofrontal cortex (Grazyna Rajkowska, Miguel-Hidalgo, Wei, Dilley, Pittman, Meltzer, Overholser, Roth, & Stockmeier, 1999). More interestingly, several studies observed significant changes in glial change while there were little to no changes regarding neuronal size or density. This data leads to the gliopathology hypothesis of depression, the idea that glial dysfunction is responsible for the disease process of MDD.
Although most studies found reduced glial density, others found an increase in glial cells in the orbitofrontal cortex (Xiaohong Si, Miguel-Hidalgo, O’Dwyer, Stockmeier, & Rajkowska, 2004). The postmortem studies have multiple limitations including: small sample size, different causes of death, and
no control for substance or alcohol abuse. More importantly multiple data was derived from the same cases, making it less likely to generalize the findings. Meta-analysis and comparisons between studies is difficult because of the use of different methodologies
The usual response of glial cells in pathological conditions is very heterogeneous. The glial cells become hypertrophic and proliferate, leading to a so-called reactive state. This process is known as gliosis and involves upregulation of GFAP and damaged neurons. In contrast to other CNS disorders, MDD is not associated with gliosis, the expression of astroglia markers is decreased and there is no prominent neuronal pathology.
Summary: Although each of the hypotheses described above show some
limitations, overall the findings are promising and may shed some light on the complexity of the neurobiology of depression. The fact that the supporting evidence is only available in part of the MDD patients might be the result of biologically distinct versions of MDD. It has been widely known that stress is a major contributory factor in the development of depression: these hypotheses shed some light how stress alters functioning in the central nervous system.
One of the most surprising findings was the abnormality in glial cells in MDD postmortem brains. The postmortem studies show robust evidence of glial pathology. The recent insight that glial cells are not just support cells for neurons, but play multiple functionally important roles, has sparked the exploration of the contribution to multiple brain diseases. Glial dysfunctions may contribute to the presentation of clinical signs or to mechanisms leading to pathological changes in the central nervous system. In the next chapter I will further describe the possible role of glial cells in MDD.
4 Glial cells: new insights
4.1 Astrocytes, oligodendrocytes and microglia
Traditionally, research that looked into diseases and disorders of the brain has been predominately focused on neuronal cells. The pathogenesis of brain-associated diseases is universally attributed to the malfunction or loss of
neurons. Meanwhile glial cells (in Greek glia means glue) were often overlooked or relegated to an undefined supportive role (G Rajkowska & Miguel-Hidalgo, 2007)].
In the last two decades, the neurocentric view has been substantially challenged by a growing body of evidence that hints that glial cells are far more functionally active and are involved in many aspects of brain physiology (Rodríguez & Verkhratsky, 2011). Glial cells can be divided into three classes: astrocytes, oligodendrocytes and microglia. These glial cells differ from each other by specific morphology and functional activity.
Figure 3: Glial cells of the CNS support neurons and maintain their environment. The glial cells include astrocytes, oligodendrocytes, and microglial cells. Astrocytes provide nutrients to neurons, maintain their extracellular environment, form the blood-brain barrier and provide structural support. Oligodendrocytes form the myelin sheath around axons. Microglia scavenge pathogens and dead cells. Figure adapted from (Allen & Barres, 2009).
Astrocytes are the most abundant of the glial cells and can be found both in the grey and white matter of the brain (Benedetto & Rupprecht, 2013). These cells are relatively large and some have a star-like appearance with elaborate processes. They form connections with other astrocytes, neurons and blood vessels. Astrocytes have a number of complex and essential functions in the central nervous system, in order to control CNS homeostasis. These functions include: supporting neuronal energy metabolism by exporting glucose or lactose, the regulation of extracellular ions, the uptake and metabolism of neurotransmitters, the production of neurotrophic factors, formation of the
blood-brain barrier, activating neurogenesis and responding to blood-brain injuries by activating reactive astrocytes.
Astrocytes are increasingly recognized as active partners of neuronal cells and interact extensively through neurotransmitters, neurotrophic factors, cytokines and gap junctions (Verkhratsky, J., & Steardo, 2013). Cell culture studies show that astrocytes express many of the same receptors as neurons, including glutamate, GABA, serotonin, dopamine, norepinephrine and histamine (Porter & ken D McCarthy, 1997; G Rajkowska & Miguel-Hidalgo, 2007). Because astrocytes have the ability to regulate the concentrations of neurotransmitters in the synaptic cleft and are able to communicate with both the presynaptic and postsynaptic neuron, they are viewed as the third element of the functional synapse, now called the tripartite synapse (Sanacora & Banasr, 2013).
Oligodendrocytes are smaller than astrocytes and have fewer and shorter processes, and can be found both in the white and grey matter of the brain. Oligodendrocytes are responsible for the “white” color of the white matter as they produce the myelin sheaths that insulate the neuronal axons (Purger, Gibson, & Monje, n.d.). Myelin has important effects on the speed of action potential conduction. Furthermore increasing evidence proposes that oligodendrocytes may also actively shape neuronal activity, through changes in sheath thickness and the internode length of myelin. As a result of myelin plasticity this affects the velocity of conduction of action potentials, and consequently synaptic plasticity.
Myelination was long thought to be a developmental process, but recent studies suggest that myelin plasticity may be sensitive to experiences in adulthood as well (Baumann & Pham-Dinh, 2001; Purger et al., n.d.). A deeper understanding of myelin plasticity and its underlying mechanisms may provide insights into diseases involving myelin damage or dysregulation. While the main function of oligodendrocytes is the formation of myelin, a type of oligodendrocyte known as the satellite oligodendrocyte are not directly connected to the myelin sheath (Baumann & Pham-Dinh, 2001). The satellite oligodendrocytes are preferentially found in gray matter and may serve to regulate the microenvironment around neurons.
Microglia form the macrophages of the brain and are first responders during changes in the structural integrity of the brain such as head trauma or infection (Jebelli, Su, Hopkins, Pocock, & a. Garden, 2015). Under these circumstances, active microglia migrate to the site of injury and become highly phagocytic towards damaged neurons or myelin. They also react to imbalances in ion homeostasis and participate in the immune response. Stress and glucocorticoids induce a pro-inflammatory response in microglia. New recently discovered functions revealed that not only the activated microglia is functionally active: the resting microglia is indicated in multiple physiologic processes such as neurogenesis, neurotransmission and the maintenance of synapses (Miller et al., 2009). Similar to astrocytes, microglia are able to induce alterations in neighboring neurotransmission.
Summary: Glial cells are essential for normal neuronal functioning, CNS
communication and immune responses. The newly discovered important functions of glial cells in healthy brains prompted researchers to consider the role of glial cells in connection to diseases. Because glial cells participate in essentially all processes vital for neuronal function and survival, glial dysfunctions may contribute to the presentation of clinical signs or to mechanisms leading to pathological changes in the CNS.
Dysfunction of all of these cells (astrocytes, oligodendrocytes, and microglia) might contribute to the pathogenesis seen in numerous CNS associated disorders, such as depression (Jo et al., 2015). As was said in the introduction I will focus the rest of the review on the role of astrocytes in the pathogenesis of depression. Because of these multiple complex functions of astrocytes they are seen as possible important regulators of neuronal function and synaptic transmission.
4.2 Astrogliopathology and MDD
The first idea that glial cell abnormalities might lead to MDD came from histopathological studies of postmortem brain tissue as was mentioned in a previous chapter. In these studies a Nissl staining technique was used that does not differentiate between the different types of glial cells.
Glial fibrillary acidic protein (GFAP) is an intermediate filament protein and an important component of the cytoskeleton in astrocytes during development. GFAP was found to be decreased in the amygdala (Altshuler et al., 2010), hippocampus (Müller et al., 2001), dlPFC (X Si, Miguel-Hidalgo, O’Dwyer, Stockmeier, & Rajkowska, 2004), OFC (Miguel-Hidalgo et al., 2000), locus coeruleus (Bernard et al., 2011), the ACC (Webster et al., 2001) and the cerebellum (Fatemi et al., 2004) of MDD patients.
Other astroglial markers such as the gap junction proteins connexins 40 and 43 (Bernard et al., 2011; Ernst et al., 2011) and water channel aquaporin-2 (AQP4) (G Rajkowska & Stockmeier, 2013) were also decreased in brain tissue from MDD patients. Glutamate transporters that are located in astrocytessuch as excitatory amino acid transporters-1 and -2 (EAAT1 and EAAT2) may also serve as markers of astrocyte functioning. These transporters appear to be dysregulated (Choudary et al., 2005; Miguel-Hidalgo et al., 2002) in MDD patients, whereas neuronal glutamate transporters are not affected (Bernard et al., 2011).
The astroglia marker calcium binding protein S100B can be assessed in vivo in the serum and cerebrospinal fluid. Damage to astroyctes causes leakage of S100B into the serum and bloodstream. Serum and cerebrospinal levels of S100B were elevated in subjects with MDD, supporting the idea of astrocytic damage or dysfunction (Schroeter et al., 2010). The in vivo findings give us an insight in a prior part of astrogliopathology, in which the astrocyte are damaged but not yet death.
These astroglial specific staining studies on post mortem brain material furthermore revealed that the alteration in astrocytes were mainly present in younger and middle aged MDD subjects (Miguel-Hidalgo et al., 2010). In patients over 60 years old there was no significant difference in glial cell density compared to age matched healthy controls. One possible explanation is that the reduction of astrocyte population is a critical part of the onset of depression, whereas the deficit is later normalized or overcompensated as pharmacological drugs are administered. Because aging itself leads to decreased GFAP expression, late onset MDD might have involve another pathophysiology.
Furthermore it was found that subjects with a long history of MDD show subtle changes in neuronal cells, the neurons seem to shrink or have reduced
dendritic branching (Cotter et al., 2001). Neurons are unable to survive and there is no possibility for synaptic remodeling without close interaction with astrocytes (Chen & Swanson, 2003). Consequently, these findings suggest that in the development of the disease the astrocytes are first affected and in a later timeframe, the dead or dysfunction of astrocytes affects the neurons.
Summary: More specific staining studies show that astrocytes are a likely culprit
underlying the pathological changes seen in the postmortem tissue of MDD patients. Furthermore the studies show that the astrocytic dysfunction is local event rather than globally distributed. These data support a model in which astrocytes function is altered at different stages of the disease process, and ultimately contributing to dysfunction or death of neurons.
5 Animal models of depression
As discussed in the previous chapter, the staining of postmortem tissue shows a reduction of astrocytic activity in MDD patients. However the precise role of the (dysfunction of) astrocytes specifically in the disease processes remains to be investigated. To further examine the role of astrocytes in the pathogenesis of MDD, informative and predictive animal models have been developed over the last decade. Animal models are important tools in exploring the underlying mechanism of neurodegenerative and neuropsychiatric diseases (Nestler & Hyman, 2010a). Besides, these models are used to examine therapeutic effects of potential drugs. Animal models of depression have been established in various species (e.g. hamsters, voles, tree shrews, primates), but preclinical psychiatric research has clearly favoured the rat as the animal model of choice. This, because of its fast reproduction, its common use in neurobiological research and its ability to perform well in cognitive and operant tasks. However more recently a shift in favour of the mouse can be seen. This is the result of newer technologies involving genetic alteration, such as transgenic lines.
The validity of animal models is normally based upon biological similarities between species. The problem with animal models of depression, or other psychiatric disorders, is the mimicking of human symptoms in an animal. Symptoms such as guilt, recurring thoughts of suicide and depressed moods are
likely to be pure human emotions that cannot be introduced in an animal. The animals are therefore assessed on replicable aspects such as anhedonia, learned helplessness, behavioral despair, appetite patterns, and disturbances in sleep (Krishnan & Nestler, 2008a). To measure the level of anhedonia, learned helplessness and behavioral despair specific paradigms are developed that are described below. Changes in appetite patterns can be measured by weight gain or loss in the animal. EEG measurements indicate changes in sleep patterns.
Figure 4 Immobility in increased in depressed rodents in the forced swim test and tail suspension test and this immobility can be reversed by acute treatment with antidepressants. Learned helplessness is induced after repeated unpredictable electric shocks. Anhedonia is measured by loss of preference of sugar water over regular water because of the loss of pleasure. Reduced exploration is often extrapolated as more anxiety in the animals. Changes in sociability can be measured to reflect impairments in natural reward or social anxiety. Picture taken from Krishnan and Nestler 2010
Anhedonia is the loss of pleasure or interest and is considered a core symptom of depression (Wilner, 1997). It is the inability to get pleasure from activities that were enjoyed before the depressive episode. In many animal models anhedonia is measured by using the sucrose preference test or intracranial self-stimulation (ICSS). Healthy animals have a distinct preference for sweetened water over regular water. Animals that show no or little preference over sweetened water are thought to show a loss of pleasure and are therefore depressed. A similar effect can be seen in
intracranial self-stimulation, by pulling a lever or adjusting a wheel, animals are able to directly stimulate their brain’s reward system. Depressed animals are less likely to reward themselves (Krishnan & Nestler, 2008b).
Learned helplessness is a paradigm that uses a stress-exposure period in which rats or mice are exposed to inescapable shocks. In a subsequent session, the animals are tested for their performance in an active avoidance test (Matthews, Christmas, Swan, & Sorrell, 2005). Usually this entails a box which delivers footshocks in a certain place, the animals are able to move to another area of the box were no shocks are given. Animals that underwent the learned helplessness paradigm show reduced abilities to escape in this model. The ability to escape is restored after antidepressant treatment.
Behavioral despair is measured by the forced-swimming test (FST) or the tail suspension test (TST) (Matthews et al., 2005). Both test are the most widely used to measure the effects of antidepressants and induce "depressive like" behavior. In the FST the animal is placed in an inescapable water tank and after an initial period of struggling, swimming and climbing the animals become immobile. The immobility in TST follows also after an initial period of struggling while the animal is dangled from its tail. The immobility is seen as an expression of behavioral despair and is reversed by acute treatment of almost all available antidepressants. Although others have argued that this behavior might be the result of involuntary defeat strategy (Sloman, 2008).
Box 1 - Animal models of depression
The main cause of depression in humans is stress. As a result almost all animal models of depression show acute or chronic stress. The most used model is based upon chronically unpredictable stress (CUS). Other common animal models of depression are based upon early life stress such as maternal deprivation studies
or social induced stress studies such as social defeat.
In the CUS paradigm animals are exposed to multiple mild stressors in a random order over a couple of weeks (Pollock, 2010). The unpredictable stressors include: small temperature reduction, changes of housing, short periods of food and water deprivation. After three weeks of exposure the animals show signs of anhedonia, weight loss, decrease in locomotor activity, lower libido, disturbed sleep patterns, reduced investigative behaviors, altered cytokine levels, altered HPA axis activity, reduced neurogenesis, and reduced BNDF expression (Nestler & Hyman, 2010b). The difference observed in this model can be reversed by chronic treatment with antidepressants (Song et al., 2006)
Early life stress is typically applied in the form of maternal separation during early postnatal developmental periods (e.g. prolonged or repeated maternal separation during the first postnatal weeks). After the early-life period the animals are allowed to develop under normal conditions (Lyons, Parker, & Schatzberg, 2010). As adults, these previously separated rats show behavioral abnormalities such as increased immobility, disturbed sleep and appetite patterns, spatial learning defects and altered HPA functioning. Some of these effects are counteracted by chronic antidepressant treatment or ECS (Ryan et al., 2009)
The social defeat stress paradigm is a widely used model. In this model, males are placed in the territory of bigger, more aggressive males. The intruders are repeatedly attacked by the bigger animals and the intruder gets (socially) defeated. After a couple of minutes they are separated by a glass door, still able to smell the other. This set up is repeated with different aggressors for multiple days. After multiple defeat encounters, rodent display reduced social integration, decreased exploration and locomotor behavior, anhedonia, increased stress-induced immobility and alteration in HPA axis, altered circadian rhythm, reduced BNDF, increased corticosterone, and inflammation factors (Nestler & Hyman, 2010b). All of these changes can be reversed by chronic administration of antidepressants (Pollak, 2010).
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Similar to findings from postmortem studies, reduced GFAP levels were found in multiple brain regions in multiple animal models of depression. For example GFAP reduction in the hippocampus was observed with regard to social defeat stress (Araya-Callís, Hiemke, Abumaria, & Flugge, 2012; Czéh, Simon, Schmelting, Hiemke, & Fuchs, 2006; Fuchs et al., 2004) and early life stress (Leventopoulos et al., 2007). Immunoreactivity of GFAP was furthermore diminished in the prefrontal cortex in the CUS model (Banasr et al., 2010) and early life stress model (Leventopoulos et al., 2007). Also the amygdala showed reduction of GFAP levels in an early life stress model . Genetically stress susceptible animal strains such as the Fischer and Wistar-Kyoto (WKY) rat models also showed GFAP reductions in the same brain regions (Smialowska, Szewczyk, Woÿniak, Wawrzak-Wlecial, & Domin, 2013) Antidepressant treatment was able to restore the GFAP levels (Liu et al., 2009) suggesting a role for astrocytes in the operating mechanism behind antidepressants. However, not all antidepressants were found to counteract the reduction of GFAP immunoreactivity, while they did alleviate the behavioral changes (Araya-Callís et al., 2012). The most consistent finding on astrocytic activation was observed after electroconvulsive shock therapy (ECT). GFAP immunoreactivity was increased in the hippocampus and amygdala of ECT exposed rats (Steward, 1994).
A significant decrease in the expression of connexin 43 was found in rats exposed to CUS (Sun, Liu, Yuan, Li, & Chen, 2012), which was reversible by the chronic administration of antidepressants. Depressive behaviors could also be induced by blockage of Cx43, a major gap junction protein in astrocytes (Sanacora & Banasr, 2013). Furthermore it was found that fluoxetine treatment resulted in up-regulated levels of connexin 43 in the PFC of rodents (Fatemi et al., 2004).
The rodent glutamate-asperate transporter (GLAST) and glial glutamate transporter 1 (GLT-1) are homologues to the human EAAT1 and EAAT-2 transporters respectively. Blockage of the GLT-1 transporters leads to anhedonia in rats (Bechtholt-Gompf et al., 2010; John et al., 2012; Y. Lee, Gaskins, Anand, & Shekhar, 2007). In contrast, another study found no alteration of GLAST or GLT-1 levels in CUS animals, although GFAP level reduction could be observed (Banasr et al., 2010). A possible explanation is that the levels of these transporters do not have to be downregulated to induce impaired functioning (Hughes, Maguire, McMinn, Scholz, & Sutherland, 2004). GFAP was found to play a key role in the trafficking of glutamate transporters and loss of GFAP results in decreased activity of these transporters.
Animal studies revealed also a more direct link with astrocyte pathology and depression. It was found that the administration of L-alpha-aminoadipic acid (L-AAA), an astrocyte specific toxin, in the PFC resulted in depressive symptoms in the sucrose intake test and forced swim test in rats (Banasr & Duman, 2008). The effects of L-AAA were similar to chronic unpredictable stress (CUS)-induced depressive-like behaviors in these tests, Suggesting that the loss astroglial cells contributes to core symptoms of depression. However, ibotenate-induced neurotoxic lesion of the PFC had no effect in these behavioral tests.
Sofrofiew et al. found that the reason for the reduced levels of GFAP immunoreactivity is unlikely to be the result of glial atrophy (Sofroniew & Vinters, 2010b). Although GFAP immunoreacitvity was found to be decreased, the total number of astrocytes did not differ when examined by Nissl staining or S100beta immunoreactivity (Sofroniew & Vinters, 2010b). However they found morphological changes in astrocytes following chronic stress. The morphological changes found were reduced length and volume of the astrocytic processes and their branching points, suggesting impaired glial functioning rather than glial
atrophy. Others have reported similar findings (Smialowska et al., 2013; Tynan, 2013).
Summary: Animal models of depression show significantly diminished cortical
and limbic astrocyte activity, as measured by several astroglial markers. Otherwise, glia specific toxins that attack astrocytes induce depressive symptoms. Furthermore these changes are likely the result of astrocyte dysfunction instead of atrophy of these cells. In the next chapter I will discuss how dysfunction of astrocytes may lead to changes observed in MDD patients.
6 How the dysfunction of astrocytes can contribute to the pathophysiology
seen in MDD
Alterations in astrocyte physiology may be involved in the pathogenesis of numerous neurological disorders. These new insights have lead to a rapidly increasing number of conditions thought to involve dysfunction of astrocytes. This includes epilepsy, amytrophic lateral sclerosis(Rothstein, Van Kammen, Levey, Martin, & Kuncl, 1995), Huntington disease (Bradford et al., 2009), Rett syndrome (Okabe et al., 2012), Alexander's disease and fragile X syndrome (Molofsk et al., 2012). In most of these conditions it is not yet clear whether the observed astroglial changes are causative of the disease or if they are the downstream result of another underlying pathophysiology.
Postmortem brain analyses and animal studies have implicated glial dysfunction, and specifically astrocyte dysfunction in MDD pathophysiology. However, little is known about the underlying etiological mechanisms linking astrocytic dysfunction to depression. We are only at the initial stages of understanding the complex role of astrocytes and the consequences of astrocyte dysfunction.
Recent studies indicate that astrocytes are heterogeneous and form a population of complex and functionally diverse cells (Oberheim, Goldman, & Nedergaard, 2012). Different brain circuits have their own physiological distinct subtype of astrocyte. Besides, it was found that during CNS insults the astrocytes can either become neuroprotective or neurotoxic, depending upon context. It is
likely that further discoveries about astrocyte function and dysfunction will hold the key to a better understanding of the pathophysiology underlying MDD.
Although the exact molecular mechanism through which astrocytes modulate depressive behaviors are not yet characterized, I will describe how astrocytic dysfunction may lead to the clinical observations seen in humans and animal models of depression. As previously mentioned, astrocytes have a central role in the tripartite synapse.
6.1 The tripartite synapse
Astrocytes completely or partially enwrap presynaptic terminals and postsynaptic spines. The overall level of coverage is believed to vary between brain regions: In the hippocampus around 60 percent of synapses are ensheathed by astrocytic processes (Ventura & Harris, 1999) and a third of synapses in the neocortex (Spacek, 1985). Astrocytic processes contain neurotransmitter receptors and transporters which corresponds to the neurotransmitters released at the synapses they ensheath (Chaudhry et al., 1995). This allows the astrocytes to quickly respond to extracellular levels of neurotransmitter (Porter & ken D McCarthy, 1997). In vitro studies showed that astrocytes extent their processes toward sources of glutamate especially (Cornell-bell, 1990b).
In contrast to neurons, astrocytes cells are not electrically excitable. However in the last couple of years it was found that astrocytes are not only able to influence neuronal communications but are also able to communicate among themselves (Verkhratsky, Rodríguez, & Steardo, 2013). Neurotransmitters released from presynaptic neurons evoke the concentrations of Ca2+ in adjacent astrocytes. These activated glia, in turn, release gliotransmitters such as glutamate, D-serine, and adenosine triphosphate (ATP), which gives feedback to either suppress or enhance the release of further neurotransmitters. Through this bi-directional communication between neurons and astrocytes, they form the tripartite synapse.
Astrocytes are able to regulate synaptic and intracellular levels of monoamines, including serotonin, norepinephrine, and dopamine. In addition, astrocytes contain the monoamine regulating enzymes MAO and catechol-O-methyltransferase (COMT). The chronic administration of antidepressant drugs, such as citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and
sertraline have been shown to inhibit the uptake of serotonin by blocking the astrocytic serontonin transporter (Schildkraut & Mooney, 2004). In vitro studies also found that selective and non-selective norepinephrine inhibitors, inhibited the astrocytic norepinephrine uptake (Inazu, Takeda, & Matsumiya, 2003). Astrocytic dysfunction at the tripartite synapse might thus lead to a change in the extracellular levels of monoamines.
6.2. The glutamergic tripartite synapse
One basic astrocytic function is the regulation of the glutamatergic system. Astrocytes are involved in the uptake of extracellular glutamate, the conversion of glutamate into glutamine via glutamate synthethase, and the release of glutamine back into the synaptic cleft.
Figure 5 the tripartite glutamate synapse. Glutamate is released into the extracellular space. Glutamate binds to ionotropica glutamate receptors (NDMA receptors), and AMPA receptors, and metabotropic glutamate receptors on the membrane of both postsynaptic neuron and astroctye. Ectracellular glutamate is cleared from the synapse through EAAT-1/EAAT-2 transporters on the astrocyte, and to a lesser degree on neuronal EEAT-3 and EAAT-4 transporters. Within the glial cells, glutamate is converted to glutamine by glutamine synthetase and is subsequently released and taken up by neurons. picture from (Berne & Levy Physiology, 6th edition).
Consequently, the loss of astrocytes results in decreased expression of glutamate transporters and a reduction in glutamate uptake, which may lead to excess glutamate in the synaptic cleft and neuronal damage. The downregulation of astroglial glutamate transporters, and consequently neuronal death is identified in Wernicke encephalopathy (Hazell, 2009) and ALS (Rothstein, 2009).
As was previously mentioned astrocytic specific glutamate transporter are a marker for astrocytic dysfunction. These specifically localized glutamate transporters are decreased in MDD patients (Choudary et al., 2005; Miguel-Hidalgo et al., 2002) and animal models of depression (Bechtholt-Gompf et al., 2010; John et al., 2012; Y. Lee, Gaskins, Anand, & Shekhar, 2007). Specifically the GLT-1 transporter was found to be implemented in the pathogenesis of MDD (Zink, 2010).
Besides glutamate homeostasis astrocytes are also involved in glutamate neurotransmission via NDMA receptor activity (Grazyna Rajkowska, O’Dwyer, Teleki, Stockmeier, & Miguel-Hidalgo, 2007). Astrocytes are an exclusive source of D-serine, a glycine agonist, important for co-activation of the NDMA receptor. By regulating the amount of D-serine available, astrocytes may regulate NDMA receptor activity. Recent post mortem studies found that specific subunits of NMDA receptions were changed in people with major depression (Feyissa, Chandran, Stockmeier, & Karolewicz, 2009).
6.3. Potential therapeutic target
Potential dysfunction of glutamate and GABA levels seen in MDD patients are likely to be involved in the pathologies observed in astrocytes. As a result multiple drugs that operate on NDMA receptors have gathered interest as potential treatment for MDD (Sanacora, Treccani, & Popoli, 2012). These include, D-cycloserine (an NMDA partial agonist), amantadine (a low affinity, noncompetitive NMDA antagonist), memantine (a low affinity, noncompetitive, voltage-dependent NMDA receptor antagonist), ketamine (a noncompetitive NMDA receptorantagonist), riluzole (a negative modulator for presynaptic conduction in glutamatergic fibers), and lamotrigine (a negative modulator for glutamate release). It was found that antidepressants that act on the glutamatergic system such as Ketamine and NMDA antagonists, not only have fast acting antidepressant properties but operate in treatment resistant patients.
Theoretically the increase of glial cell density would benefit energy for neurons, trophic support, improved glutamatergic neurotranspission, and enhanced synaptic functioning. Antidepressant therapies may augment astrocytes and improve their functioning in the tripartite synapse.
Summary: Despite the progress of understanding the importance of astrocytes
in the last few decades, we are only at the initial stage of understanding the astroglia and their interaction with neurons. Because of the involvement of astrocytes in multiple aspects of brain homeostasis, dysfunction of astrocytic function could have detrimental effects. The astrocyte abnormalities observed in postmortem, in vivo, and animal model studies are now well documented.
Conclusion
Clinical depression is the most common mental health problem, and poses an increasing burden on society. Besides, current treatment options are not effective in a substantial group of treatment seeking patients. Sadly, despite decades of research into depression’s underlying neurobiology, the newest drugs released on to markets today only vary from their predecessors in side-effect profile, with negligible improvements in efficacy.
Because of the heterogeneity of MDD it is possible that there are not only distinct biological subtypes of depression, but that each of these subtypes has its own effective drug mechanism. This can explain why some findings such as the dysfunction of HPA axis is seen in only some of the patients, and why the current available drugs are effective in part of the MDD population.
In order to find new potential therapeutic targets a better understanding of the etiology of MDD is necessary. The monoaminergic hypothesis was found to be an incomplete explanation of the pathophysiology of depression. Multiple new hypotheses have been proposed, but have failed to produce a winner. Abnormalities in glial cells are a well-established finding in MDD research. In addition, multiple studies have indicated a link between depressive symptoms and functionally impaired astrocytes. Although oligodendrocytes and microglia are also likely to play a role.
A re-examination of depression and its pathophysiology through the lens of astrogliopathology may lead to a more complete understanding of the disorder and may improve new therapeutic strategies. Although recent studies have revealed that astrocytes and other glial cells are far more functionally active than previously thought, there is still a lot that remains to be discovered. Preliminary indications suggest that astrocytes can be divided into subclasses with its own functional profile. Furthermore these subclasses can be found in different regions of the brain. Further research is necessary to reveal what the exact differences are between these astrocytes and might explain why different brain regions are differently affected.
Although the exact mechanism underlying the neurobiology of MDD is not yet understood, the role of astrocyte dysfunction is becoming more and more apparent. Specifically the disturbed glutamate homeostasis and the role of the astrocyte herein.
Future research directions may elaborate further on the role of astroglial cell dysfunction and glutamate homeotasis, neurogenesis and neuroplasticity. Individual difference to stress response may likely lead to different reaction of MDD subtypes (inflammation, HPA-axis, astroglia dysfunction). Astrocytic dysfunction could also reduce metabolic support for neurons, making them more vulnerable to excitotoxic damage and functionally impaired. Initial findings support a role of astoryctic dysfunction in the regulation of neurogenesis (Kong, 2013)
There is also evidence for astrocyte influence in the process of neuroplasticity. Astrocytes synthesize and release several growth factors, including BDNF, that are important in neuronal survival, growth and differentiation and synaptic plasticity. Chronic antidepressant treatment and electroshock therapy were found to increase the expression of BDNF and other neurotrophic factors derived from astrocytes (mojca-juric 2006). Impaired functionally of astrocytes could therefore lead to a reduction of neurotropic factors.
Future research may also shed light in the potential therapeutic effects of targeting astrocytes. Whether or not drugs based upon astrocyte dysfunction might be the long awaited answer and are not only effective and have fewer side-effect but could potentially shrink the observed therapeutic time gap.
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